In 2016, orphan drug designation was assigned to the compound in the US. for the treatment of stage IIB-IV melanoma

EpacadostatAn orally available hydroxyamidine and inhibitor of indoleamine 2,3-dioxygenase (IDO1), with potential immunomodulating and antineoplastic activities. epacadostat targets and binds to IDO1, an enzyme responsible for the oxidation of tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, epacadostat increases and restores the proliferation and activation of various immune cells, including dendritic cells (DCs), NK cells, and T-lymphocytes, as well as interferon (IFN) production, and a reduction in tumor-associated regulatory T cells (Tregs). Activation of the immune system, which is suppressed in many cancers, may inhibit the growth of IDO1-expressing tumor cells. IDO1 is overexpressed by a variety of tumor cell types and DCsINCB24360 (epacadostat), An Agent For Cancer Immunotherapy

Incyte and Merck Expand Clinical Collaboration to Include Phase 3 Study Investigating the Combination of Epacadostat with Keytruda® (pembrolizumab) as First-line Treatment for Advanced Melanoma

Pivotal study to evaluate Incyte’s IDO1 inhibitor in combination with Merck’s anti-PD-1 therapy in patients with advanced or metastatic melanoma

WILMINGTON, Del. and KENILWORTH, N.J. — October 13, 2015 — Incyte Corporation (Nasdaq: INCY) and Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the expansion of the companies’ ongoing clinical collaboration to include a Phase 3 study evaluating the combination of epacadostat, Incyte’s investigational selective IDO1 inhibitor, with Keytruda® (pembrolizumab), Merck’s anti-PD-1 therapy, as first-line treatment for patients with advanced or metastatic melanoma. The Phase 3 study, which is expected to begin in the first half of 2016, will be co-funded by Incyte and Merck.

“We are very pleased to expand our collaboration with Merck and to move the clinical development program for epacadostat in combination with Keytruda into Phase 3,” said Hervé Hoppenot, President and Chief Executive Officer of Incyte. “We believe the combination of these two immunotherapies shows promise and, if successfully developed, may help to improve clinical outcomes for patients with metastatic melanoma.”

“The initiation of this large Phase 3 study with Incyte in the first-line advanced melanoma treatment setting is an important addition to our robust immunotherapy clinical development program for Keytruda,” said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. “We continue to explore the benefit that Keytruda brings to patients suffering from advanced melanoma when used alone, and we are pleased to be able to add this important combination study with epacadostat to our Keytruda development program.”

Under the terms of the agreement Incyte and Merck have also agreed, for a period of two years, not to initiate new pivotal studies of an IDO1 inhibitor in combination with a PD-1/PD-L1 antagonist as first-line therapy in advanced or metastatic melanoma with any third party. During this time, the companies will each offer the other the opportunity to collaborate on any new pivotal study involving an IDO1 inhibitor in combination with a PD-1/PD-L1 antagonist for types of melanoma and lines of therapy outside of the current collaboration agreement.

The agreement is between Incyte and certain subsidiaries and Merck through its subsidiaries.

Epacadostat and Keytruda are part of a class of cancer treatments known as immunotherapies that are designed to enhance the body’s own defenses in fighting cancer; the two therapies target distinct regulatory components of the immune system. IDO1 is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Preclinical evidence suggests that the combination of these two agents may lead to an enhanced anti-tumor immune response compared with either agent alone.

Safety and efficacy data from the ongoing Phase 1/2 study evaluating the combination of epacadostat with Keytruda in patients with advanced malignancies is scheduled to be highlighted as a late-breaking oral presentation (Abstract #142) at the upcoming Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting & Associated Programs, November 4–8, 2015 at the Gaylord National Resort & Convention Center in National Harbor, MD.

Metastatic Melanoma

Melanoma, the most serious form of skin cancer, strikes adults of all ages and accounts for approximately five percent of all new cases of cancer in the United States each year. The number of new cases of melanoma continues to rise by almost three percent each year which translates to 76,000 new cases yearly in the U.S. alone.[i] The 5-year survival rate for late-stage or metastatic disease is 15 percent.[ii]

About Epacadostat (INCB024360)

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. Epacadostat is an orally bioavailable small molecule inhibitor of IDO1 that has nanomolar potency in both biochemical and cellular assays and has demonstrated potent activity in enhancing T lymphocyte, dendritic cell and natural killer cell responses in vitro, with a high degree of selectivity. Epacadostat has shown proof-of-concept clinical data in patients with unresectable or metastatic melanoma in combination with the CTLA-4 inhibitor ipilimumab, and is currently in four proof-of-concept clinical trials with PD-1 and PD-L1 immune checkpoint inhibitors in a variety of cancer histologies.

[00184] Malononitrile (320.5 g, 5 mol) was added to water (7 L) preheated to 45 °C and stirred for 5 min. The resulting solution was cooled in an ice bath and sodium nitrite (380 g, 5.5 mol) was added. When the temperature reached 10 °C, 6 N hydrochloric acid (55 mL) was added. A mild exothermic reaction ensued with the temperature reaching 16 °C. After 15 min the cold bath was removed and the reaction mixture was stirred for 1.5 hrs at 16-18 °C. The reaction mixture was cooled to 13 °C and 50% aqueous hydroxylamine (990 g, 15 mol) was added all at once. The temperature rose to 26 °C. When the exothermic reaction subsided the cold bath was removed and stirring was continued for 1 hr at 26-27 °C, then it was slowly brought to reflux. Reflux was maintained for 2 hrs and then the reaction mixture was allowed to cool overnight. The reaction mixture was stirred in an ice bath and 6 N hydrochloric acid (800 mL) was added in portions over 40 min to pH 7.0. Stirring was continued in the ice bath at 5 °C. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (50 °C) to give the desired product (644 g, 90%). LCMS for C3H6N5O2

(M+H)+: m/z = 144.0. 13C MR (75 MHz, CD3OD): δ 156.0, 145.9, 141.3. Step 2: 4-Amino-N-hydroxy-l,2,5-oxadiazole-3-carboximidoyl chloride [00185] 4-Amino-N,-hydroxy-l ,2,5-oxadiazole-3-carboximidamide (422 g, 2.95 mol) was added to a mixture of water (5.9 L), acetic acid (3 L) and 6 Ν hydrochloric acid (1.475 L, 3 eq.) and this suspension was stirred at 42 – 45 °C until complete solution was achieved. Sodium chloride (518 g, 3 eq.) was added and this solution was stirred in an ice/water/methanol bath. A solution of sodium nitrite (199.5 g, 0.98 eq.) in water (700 mL) was added over 3.5 hrs while maintaining the temperature below 0 °C. After complete addition stirring was continued in the ice bath for 1.5 hrs and then the reaction mixture was allowed to warm to 15 °C. The precipitate was collected by filtration, washed well with water, taken in ethyl acetate (3.4 L), treated with anhydrous sodium sulfate (500 g) and stirred for 1 hr. This suspension was filtered through sodium sulfate (200 g) and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in methyl i-butyl ether (5.5 L), treated with charcoal (40 g), stirred for 40 min and filtered through Celite. The solvent was removed in a rotary evaporator and the resulting product was dried in a vacuum oven (45 °C) to give the desired product (256 g, 53.4%). LCMS for C3H4CIN4O2 (M+H)+: m/z = 162.9. 13C NMR (100 MHz, CD3OD): 5 155.8, 143.4, 129.7.

To a solution of 2-({4-[4-(3-bromo-4-f uorophenyl)-5-oxo-4,5-dihydro-l ,2,4- oxadiazol-3-yl]-l ,2,5-oxadiazol-3-yl}amino)ethyl methanesulfonate (2.13 kg, 4.6 mol, containing also some of the corresponding bromo-compound) in dimethylformamide (4 L) stirring in a 22 L flask was added sodium azide (380 g, 5.84 mol). The reaction was heated at 50 °C for 6 h, poured into ice/water (8 L), and extracted with 1 : 1 ethyl acetate:heptane (20 L). The organic layer was washed with water (5 L) and brine (5 L), and the solvents removed in vacuo to afford the desired product (1464 g, 77%) as a tan solid. LCMS for CnHgBrFNsOs a

1.2.5- oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one (500 g, 1.22 mol) in methanol (6 L). The mixture was allowed to stir for 30 min during which time a mild exotherm was observed. Chlorotrimethylsilane (930 mL, 7.33 mol) was added as a solution in methanol (1 L) dropwise at a rate so that the temperature did not exceed 35 °C, and the reaction was allowed to stir for 3.5 h at ambient temperature. The reaction was neutralized with 33 wt% solution of sodium thiosulfate pentahydrate in water (-1.5 L), diluted with water (4 L), and the pH adjusted to 9 carefully with solid potassium carbonate (250 g – added in small portions: watch foaming). Di-ieri-butyl dicarbonate (318 g, 1.45 mol) was added and the reaction was allowed to stir at room temperature. Additional potassium carbonate (200 g) was added in 50 g portions over 4 h to ensure that the pH was still at or above 9. After stirring at room temperature overnight, the solid was filtered, triturated with water (2 L), and then MTBE (1.5 L). A total of 11 runs were performed (5.5 kg, 13.38 mol). The combined solids were triturated with 1 : 1 THF:dichloromethane (24 L, 4 runs in a 20 L rotary evaporator flask, 50 °C, 1 h), filtered, and washed with dichloromethane (3 L each run) to afford an off- white solid. The crude material was dissolved at 55 °C tetrahydrofuran (5 mL/g), treated with decolorizing carbon (2 wt%) and silica gel (2 wt%), and filtered hot through celite to afford the product as an off-white solid (5122 g). The combined MTBE, THF, and dichloromethane filtrates were concentrated in vacuo and chromatographed (2 kg silica gel, heptane with a 0-100% ethyl acetate gradient, 30 L) to afford more product (262 g). The combined solids were dried to a constant weight in a convection oven (5385 g, 83%).

In a 22 L flask was charged hydrogen chloride (4 N solution in 1 ,4-dioxane, 4 L, 16 mol). tert-Butyl [2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l ,2,4- oxadiazol-3-yl]-l ,2,5-oxadiazol-3-yl}amino)ethyl]carbamate (2315 g, 4.77 mol) was added as a solid in portions over 10 min. The slurry was stirred at room temperature and gradually became a thick paste that could not be stirred. After sitting overnight at room temperature, the paste was slurried in ethyl acetate (10 L), filtered, re-slurried in ethyl acetate (5 L), filtered, and dried to a constant weight to afford the desired product as a white solid (combined with other runs, 5 kg starting material charged, 41 13 g, 95%). LCMS for

Malononitrile [Aldrich, product # M1407] (320.5 g, 5 mol) was added to water (7 L) preheated to 45 0C and stirred for 5 min. The resulting solution was cooled in an ice bath and sodium nitrite (380 g, 5.5 mol) was added. When the temperature reached 10 0C, 6 N hydrochloric acid (55 mL) was added. A mild exothermic reaction ensued with the temperature reaching 16 0C. After 15 min the cold bath was removed and the reaction mixture was stirred for 1.5 hrs at 16-18 0C. The reaction mixture was cooled to 13 0C and 50% aqueous hydroxylamine (990 g, 15 mol) was added all at once. The temperature rose to 26 0C. When the exothermic reaction subsided the cold bath was removed and stirring was continued for 1 hr at 26-270C, then it was slowly brought to reflux. Reflux was maintained for 2 hrs and then the reaction mixture was allowed to cool overnight. The reaction mixture was stirred in an ice bath and 6 N hydrochloric acid (800 mL) was added in portions over 40 min to pH 7.0. Stirring was continued in the ice bath at 5 0C. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (50 0C) to give the desired product (644 g, 90%). LCMS for C3H6N5O2 (M+H)+: m/z = 144.0. 13C NMR (75 MHz, CD3OD): δ 156.0, 145.9, 141.3. Step B: 4-Amino-N-hydroxy-l,2,5-oxadiazole-3-carboximidoyl chloride

4-Amino-N’-hydroxy-l,2,5-oxadiazole-3-carboximidamide (422 g, 2.95 mol) was added to a mixture of water (5.9 L), acetic acid (3 L) and 6 Ν hydrochloric acid (1.475 L, 3 eq.) and this suspension was stirred at 42 – 45 0C until complete solution was achieved. Sodium chloride (518 g, 3 eq.) was added and this solution was stirred in an ice/water/methanol bath. A solution of sodium nitrite (199.5 g, 0.98 eq.) in water (700 mL) was added over 3.5 hrs while maintaining the temperature below 0 0C. After complete addition stirring was continued in the ice bath for 1.5 hrs and then the reaction mixture was allowed to warm to 15 0C. The precipitate was collected by filtration, washed well with water, taken in ethyl acetate (3.4 L), treated with anhydrous sodium sulfate (500 g) and stirred for 1 hr. This suspension was filtered through sodium sulfate (200 g) and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in methyl f-butyl ether (5.5 L), treated with charcoal (40 g), stirred for 40 min and filtered through Celite. The solvent was removed in a rotary evaporator and the resulting product was dried in a vacuum oven (45 0C) to give the desired product (256 g, 53.4%). LCMS for C3H4ClN4O2(M+H)+: m/z = 162.9. 13c NMR (100 MHz, CD3OD): δ 155.8, 143.4, 129.7.

To a solution of 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-l,2,5-oxadiazol- 3-yl}-l,2,4-oxadiazol-5(4H)-one (1.5 kg, 3.9 mol, containing also some of the corresponding bromo-compound) in ethyl acetate (12 L) was added methanesulfonyl chloride (185 mL, 2.4 mol) dropwise over 1 h at room temperature. Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 min, during which time the reaction temperature increased to 35 0C. After 2 h, the reaction mixture was washed with water (5 L), brine (I L), dried over sodium sulfate, combined with 3 more reactions of the same size, and the solvents removed in vacuo to afford the desired product (7600 g, quantitative yield) as a tan solid. LCMS for

Sodium iodide (1080 g, 7.2 mol) was added to 3-{4-[(2-azidoethyl)amino]-l,2,5-oxadiazol-3- yl}-4-(3-bromo-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (500 g, 1.22 mol) in methanol (6 L). The mixture was allowed to stir for 30 min during which time a mild exotherm was observed. Chlorotrimethylsilane (930 mL, 7.33 mol) was added as a solution in methanol (1 L) dropwise at a rate so that the temperature did not exceed 35 0C, and the reaction was allowed to stir for 3.5 h at ambient temperature. The reaction was neutralized with 33 wt% solution of sodium thiosulfate pentahydrate in water (~1.5 L), diluted with water (4 L), and the pΗ adjusted to 9 carefully with solid potassium carbonate (250 g – added in small portions: watch foaming). Di-fe/t-butyl dicarbonate (318 g, 1.45 mol) was added and the reaction was allowed to stir at room temperature. Additional potassium carbonate (200 g) was added in 50 g portions over 4 h to ensure that the pΗ was still at or above 9. After stirring at room temperature overnight, the solid was filtered, triturated with water (2 L), and then MTBE (1.5 L). A total of 11 runs were performed (5.5 kg, 13.38 mol). The combined solids were triturated with 1 : 1 TΗF:dichloromethane (24 L, 4 runs in a 20 L rotary evaporator flask, 50 0C, 1 h), filtered, and washed with dichloromethane (3 L each run) to afford an off- white solid. The crude material was dissolved at 55 0C tetrahydrofuran (5 mL/g), treated with decolorizing carbon (2 wt%) and silica gel (2 wt%), and filtered hot through celite to afford the product as an off-white solid (5122 g). The combined MTBE, THF, and dichloromethane filtrates were concentrated in vacuo and chromatographed (2 kg silica gel, heptane with a 0-100% ethyl acetate gradient, 30 L) to afford more product (262 g). The combined solids were dried to a constant weight in a convection oven (5385 g, 83%).

In a 22 L flask was charged hydrogen chloride (4 N solution in 1,4-dioxane, 4 L, 16 mol). fert-Butyl [2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl]- l,2,5-oxadiazol-3-yl}amino)ethyl]carbamate (2315 g, 4.77 mol) was added as a solid in portions over 10 min. The slurry was stirred at room temperature and gradually became a thick paste that could not be stirred. After sitting overnight at room temperature, the paste was slurried in ethyl acetate (10 L), filtered, re-slurried in ethyl acetate (5 L), filtered, and dried to a constant weight to afford the desired product as a white solid (combined with other runs, 5 kg starting material charged, 4113 g, 95%). LCMS for C12HnBrFN6O3 (M+H)+: m/z

142662] (149 mL, 1.72 mol) and dichloromethane (1.5 L) and cooled using an ice bath to 2 0C. tert-Butanol (162 mL, 1.73 mol) in dichloromethane (200 mL) was added dropwise at a rate so that the temperature did not exceed 10 0C. The resulting solution was stirred at room temperature for 30-60 min to provide tert-butyl [chlorosulfonyljcarbamate.

Incyte’s Andrew P. Combs presented the company’s clinical candidate for cancer immunotherapy. The basic tenet of this burgeoning field is that the human body’s immune system is a tremendous resource for fighting disease; scientists just need to figure out how to unleash it. One target that’s proven to be particularly attractive for this purpose in recent years is indoleamine-2,3-dioxygenase-1, or IDO1 (C&EN, April 6, page 10).

IDO1 plays a role in signaling the immune system to stand down from attacking foreign bodies it might otherwise go after, such as fetuses. Tumors also produce IDO1 to evade the immune system, so molecules that can inhibit this enzyme could bring the full force of the body’s defenses to bear on these deadly invaders.

Incyte’s search for an IDO1 inhibitor began with a high-throughput screen, which led to a proof-of-concept compound. But the compound had poor oral bioavailability. What’s more, the molecule and its analogs underwent glucuronidation during its metabolism: Enzymes tacked on a glucuronic acid group to the structure’s amidoxime, which was key to its activity.

The chemists reasoned they could block this metabolism by sterically hindering that position. Making such molecules proved to be more difficult than they expected. But then they unearthed a Latvian paper from 1993 that gave them the synthetic method they needed to make the series of compounds that would lead to their clinical candidate INCB24360 (epacadostat).

With its furazan core, as well as its amidoxime, bromide, and sulfuric diamide functional groups, INCB24360 is something of an odd duck, Combs acknowledged. “Some of you in the audience may be looking at this and saying, ‘That molecule does not look like something I would bring forward or maybe even make,’ ” he said, noting that the structure breaks many medicinal chemistry rules. “We’re a data-centric company, and we followed the data, not the rules,” Combs told C&EN.

The compound has completed Phase I clinical trials and is now being used in collaborative studies with several other pharmaceutical companies that combine INCB24360 with other cancer immunotherapy agents.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
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The first continuous flow synthesis of C8–C16 alkane fuel precursors from biobased platform molecules is reported. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) was found to be a recyclable and highly efficient organic base catalyst for the aldol condensation of furfural with carbonyl compounds, and the selectivity of mono- or difuryl product can be easily regulated by adjusting […]

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